It has been known that 2'-deoxy-2'-methylidenecytidine (hereinafter sometimes abbreviated as DMDC), acid addition salts thereof and hydrates thereof are useful as antitumor agents (Japanese Patent Unexamined Publication Nos. 258818/1988, 138292/1990 and 240794/1991).
A DMDC dihydrate has been confirmed to exhibit superior antitumor effects and is in use in clinical situations as an injection (Japanese Patent Unexamined Publication No. 240731/1991). An administration route by injection not only burdens patients with pain but is associated with difficulties in terms of topical injuries at the injection site and the need for regular visit to the hospital for medical treatments. Hence, the development of an oral agent which resolves these problems has been desired.
For this end, the present inventors have done a multitude of basic experiments and found that an increase in dose results in a marked decrease in oral absorption, as a result of which bioavailability of DMDC dihydrate becomes low. To be specific, a radioactively labeled DMDC dihydrate was orally administered to rats, and urinary excretion thereof (% relative to dose) within 24 hours was examined to determine the oral absorption of DMDC dihydrate. As a result, the percent excretion was 74.4.+-.1.4% at the dose of 3 mg/kg and decreased to 47.2.+-.9.6% at the dose of 30 mg/kg. For sufficient pharmacological action to be exerted by oral administration, an appropriate treatment should desirably be applied during preparation to promote the oral absorption of DMDC dihydrate.
As the absorption promoter used for improving oral absorption, there have been known fatty acids having 8 to 14 carbon atoms such as sodium caprate. Then, a composition containing sodium caprate and DMDC dihydrate was studied only to find no improvement in the oral absorption.
Also, surfactants are used for liquid agents and semi-liquid agents for improving wettability of the drug to water. It is not generally practiced, however, to add a surfactant to DMDC dihydrate of the present invention which is a solid preparation and has high wettability to water. Moreover, addition of non-ionic surfactant such as polyoxyethylene hydrogenated castor oil and polyoxyethylene (20) sorbitan monoleate did not lead to an improvement in oral absorption.
In contrast, when sodium oleate or sodium lauryl sulfate was added, absorption in situ improved, whereas urinary excretion in vivo was problematically poor, Accordingly, preparations containing these compounds pose problems in terms of stability and mucosal disorders.
It is therefore an object of the present invention to provide an antitumor composition improved in oral absorption, comprising a 2'-deoxy-2'-methylidenecytidine compound represented by DMDC dihydrate.